Surprisingly we found that the carbohydrate component of mixed meals is responsible for the strongest stimulation of GLP-1 secretion, whereas for PYY stimuli are more complex. Simple monosaccharides including glucose in particular are important, but more complex carbohydrates (e.g. isomaltulose) and also combinations with glycosidase inhibitors in healthy subjects can mimic the profiles after RYGB. We mapped the intestinal bile kinetics after RYGB and identified the bile salts as major players for both ileal and colonic hormone secretion. Bile and lipids are particularly important for neurotensin secretion, but even very high infusions rates of neurotensin had very little effect on appetite and food intake. Studies in RYGB and Sleeve Gastrectomy patients with bile acid sequestrants (cholesevelam) for several weeks are currently being performed. If bile is indeed essential for weight loss and diabetes resolution , this should impair both glucose control and weight maintenance. We identified somatostatin as the most powerful regulator of GLP-1 secretion. And we have identified somatostatin subtype 5 receptor antagonists as potential agents for obesity/diabetes treatment, a project which we are currently following up with clinical studies. Other results clearly point to the amino acid transporter Pept-1 with subsequent basolateral calcium sensing receptor activation as being essential for protein stimulation of GLP-1 secretion. GPR 142 activation caused GIP secretion but was ineffective regarding GLP-1 and PYY secretion. Currently we are mapping the contribution of each of the dietary amino acids. Surprisingly, we identified in both rodents and in humans a release after bypass from the distal ileum of secretin, and this may have metabolic consequences. Regarding the colon, we will look at metabolites generated by the intestinal microbiota, suggested to act on metabolism via secretion of gut hormones. We continue to work on the development of co-agonists/combinations of gut hormones for the treatment of obesity/diabetes, currently in collaboration with Imperial College London regarding triple agonism (PYY, oxyntomodulin and GLP-1). Extensive comparative studies of sleeve gastrectomy (SG) and RYGB suggested involvement of GIP and ghrelin in SG. We have recently performed experiments with a GIP receptor antagonist, developed in our lab and suitable for human use, which in combination with a GLP-1 antagonist clearly demonstrated the superior importance of GLP-1 for the results obtained with gastric bypass, whereas GIP is more important in healthy controls and after sleeve gastrectomy. We also look at the role of ghrelin by restoring levels by infusions in operated patients (which is important for insulin secretion it turns out). We have also completed both metabolomics and proteomics studies , the results of which need further digestion. We recently could definitively weaken the decretin hypothesis supported by many (the upper gut hypothesis) showing that the favorite candidate neuromedin U was unlikely to play a role. We also studied studies of changes in the gut microbiota after RYGB. Our study of lipids as stimuli for gut hormone secretion, the first of its kind, is out and showed that also lipid digestion is accelerated and a hierarchy for lipid components to stimulate gut hormones was established. We identified FGF 19 as possible metabolic factor, and now use isolated perfused intestine to investigate FGF 19 secretion further and FGF 19 was identified associated in a clinical study with proteomics analysis in RYGB patients with and without hypoglycemia. Our tracer studies in the operated patients have given us accurate and detailed information about the postoperative kinetics of nutrient flow (e. g. an extensive study published in the prestigious journal Gastroenterology, comparing digestion and absorption of meals in SG and RYGB patients). We have performed major randomized longitudinal studies comparing consecutive SG and RYGB patients with Norwegian colleagues (emphasizing the importance of GLP-1 secretion ofr the superiority of bypass compared to sleeve gastrectomy) and we completed a major study of responder-non-responders to RYGB using sham-feeding technology and pancreatic polypeptide responses to study vagal function, as well as somatostatin-induced inhibition of the gut hormone secretion (now published in major journal) . Responders showed markedly enhanced ad lib food intake, whereas the non-responders did not react at all. Thus, non-responsiveness is due to insensitivity to the anorectic gut hormones, clearly pointing to differential probably genetic receptive mechanisms, which , in spite of major efforts, could not be identified! However these efforts will be continued using deeper sequencing of the receptor genes.
